For many people with diabetes, especially those with Type I diabetes, insulin pump therapy, also known as continuous subcutaneous insulin infusion, is preferable to injection therapy because greater flexibility and better blood glucose control are possible with an insulin pump. Insulin pumps offer their users the means to conveniently infuse insulin in an essentially continuous manner to satisfy basal insulin needs and also in various bolus modes to satisfy meal-related insulin needs and to correct hyperglycemia at any time.
Convenience is a considerable advantage that contributes to the superior flexibility and blood glucose control that insulin pump therapy enables. For example, insulin pump convenience manifests itself as an advantage when the user has incomplete knowledge of the content and timing of a meal before it begins. The barrier to dosing additional insulin with an insulin pump is lower than with injection therapy because all that is required to infuse more insulin is a few button presses. Shortly before the start of a poorly defined meal, an insulin pump user can infuse a minimum amount of insulin in time to prevent a rapid rise in blood glucose concentration (BGC), and then he can conveniently infuse more insulin if needed, and as needed as many times as he likes, as his understanding of the meal increases. This helps an insulin pump user, as compared with a patient on injection therapy, to enjoy greater flexibility and maintain better blood glucose control during and after meals about which he has incomplete knowledge at their beginning.
Another major advantage of insulin pump therapy over injection therapy derives from the fact that typically, only a rapid-acting type of insulin is infused with an insulin pump, whereas in injection therapy an intermediate or long-acting insulin is always included to satisfy basal insulin needs. Rapid-acting insulin action peaks only 1-2 hours after infusion and vanishes 3-5 hours after infusion, while intermediate and long-acting insulins provide insulin action that lasts much longer with peaks at least 4 hours after injection. Because in insulin pump therapy the timing and amount of insulin infusion are completely flexible and the insulin is rapid-acting, the timing and intensity of insulin action may be tailored more precisely to insulin need than with injection therapy. Precision in the timing and intensity of insulin action is advantageous, not only during and after meals, which in insulin pump therapy are managed by supplementing basal insulin infusion with insulin boluses, but also in conjunction with increased physical activity, which can require a decrease from the usual amount of basal insulin. With an insulin pump infusing a rapid-acting insulin, a well-timed suspension or decrease of basal insulin delivery can often prevent hypoglycemia due to increased physical activity. In contrast, with injection therapy, because an intermediate or long-acting insulin is included to satisfy basal insulin needs, consumption of carbohydrate is often the only recourse to prevent hypoglycemia.
A further advantage of insulin pump therapy is that it provides a means to preprogram precise and predictable changes in basal insulin hours in advance, such as an increase in the early morning hours to accommodate the greater insulin need caused by the “dawn phenomenon”. With injection therapy, such changes are not as predictable and not as adjustable in amount. These and other differences between insulin pump therapy and injection therapy have made insulin pump therapy deservedly very popular.
The advantages of insulin pump therapy do not by themselves, however, guarantee good blood glucose control because figuring the timing and amount of insulin dosing necessary for good BGC control is very challenging for human beings, as well as for automated control systems which are now in experimental development. At present it remains the responsibility of the user to make all decisions about insulin dosing and food consumption to control BGC. Moreover, even when fully automated control systems become widely available, it is likely that some degree of user oversight, with the ability to intervene, will be desirable. Therefore, to most effectively manage BGC, it is important for a user to both develop the skill of estimating insulin need and also to acquire frequent feedback from a glucose monitor so that he can compensate for errors in his estimation of insulin need. Such errors occur because the amount of insulin needed is a function of variables that typically are not precisely known, including insulin sensitivity, food quantity and composition, physical activity level, the amount of insulin already in the subcutaneous tissue and blood, and the blood concentrations of other hormones. Moreover, even if all of these variables were known precisely, good algorithms for calculating the amount of insulin needed are not available. The commonly employed insulin-to-carbohydrate ratio concept, in which the amount of insulin needed for a meal is proportional to the amount of carbohydrate eaten, provides only a rough first approximation of the amount of insulin required; the major reason for this is that it only considers the carbohydrate content of food, but other nutrients affect BGC as well. Even a highly skilled insulin pump user may err significantly in his first estimation of insulin needed for a meal because it is not uncommon for a person with Type I diabetes to require meal-related insulin in an amount ten or more times the amount that would shift his BGC from above to below the normal range. Consequently, a mere 5-10% discrepancy between the amount of insulin needed for a meal and the amount of insulin infused for that meal can result in hypo- or hyperglycemia by the time the meal and the insulin have finished exerting their effects on BGC. Moreover, even if the amount of insulin dosed for a meal is correct, transient hyper- or hypoglycemia can occur due to temporary imbalances between meal and insulin effects. These difficulties underscore the importance of acquiring frequent feedback from a glucose monitor. Fortunately, frequent feedback has become possible because improved, nearly painless, point-in-time (conventional) glucose monitors and truly practical continuous glucose monitors are now available. Today, an insulin pump user measures BGC at least six, and often many more times per day, with each measurement providing an opportunity to adjust BGC up or down. In many circumstances, BGC may be measured at intervals of two hours or less. This is particularly useful in the aftermath of infusions of large amounts of insulin, for instance after a large, unfamiliar meal because with such frequent BGC monitoring, an insulin pump user can make an early assessment of how well his insulin dosing matches the insulin need created by his meal.
However, despite the advantages afforded by insulin pump therapy and the availability of frequent BGC data, the consistent maintenance of BGC within the target range is nearly impossible, especially in the context of a flexible lifestyle. One reason for this is that the pharmacodynamic effect of even rapid-acting insulins, when dosed subcutaneously, is slower than the effect of many foods on BGC. As a result, even if an insulin pump user infuses insulin in advance of a meal, if he underestimates the amount of insulin needed at that time, BGC will rise above the target range, at least transiently. While continuous BGC data could allow a user to take corrective action as soon as rising BGC signals impending hyperglycemia, even continuous BGC data does not alert the user to impending hyperglycemia early enough to prevent it when the effect of a food on BGC is faster than the pharmacodynamic effect of the insulin infused.
The pharmacodynamic profile of rapid-acting insulins creates another difficulty when BGC is frequently monitored. Because even rapid-acting insulins do not finish exerting their effects for three to five hours after dosing, in order for an insulin pump user to make use of BGC data within three to five hours after an insulin bolus, he must understand how much insulin action is to be expected from insulin already dosed, and his plans must consider that anticipated insulin action in order to avoid hypoglycemia. To address this issue, several insulin pump manufacturers produce insulin pumps that include a feature that calculates and displays “insulin on board”, abbreviated here as IOB, and also known as “bolus-on-board”, “active insulin” or “unused bolus insulin”. This feature warns a user when IOB from recent insulin boluses may still be exerting its effect and thus offers a means to predict BGC, although for reasons discussed below, such predictions using methods described in the art are not sufficiently accurate.
Because of the complexity and difficulty of predicting and managing BGC, there remains a need for new tools that assist patients in accomplishing these important tasks. This specification describes a new method and system for predicting and managing blood glucose concentration.
Description of the Related Art and Definition of Pharmacodynamic Insulin Unit Equivalents and Related Expressions
The following references disclose art relevant to embodiments of the present invention: U.S. Pat. No. 6,925,393; U.S. Pat. No. 5,822,715; U.S. Pat. No. 6,379,301; US 2006/137695; U.S. Pat. No. 6,835,175; US 2005/021006; US 2005/245904; US 2005/022274; US 2005/030164; US 2005/049179; US 2003/028089; US 2004/193025; US 2004/220517; US 2006/173406; US 2004/152622; US 2005/065465; CA 2555749; US 2005/272640; B. W. Bequette, et al., Diabetes Technology & Therapeutics 2004, 6, 868-873; D. R. L. Worthington, Medical Informatics 1997, 22, 5-19; B. W. Bequette, et al., Diabetes Technology & Therapeutics 2005, 7, 28-47; G. M. Steil, et al., Diabetes Technology & Therapeutics 2005, 7, 94-108; T. M. Gross, et al., Diabetes Technology & Therapeutics 2003, 5, 365-369; H. A. Wolpert, J. Diabetes Sci. Technol., 2007, 1, 146-150; Smart Pumping: A Practical Approach to Mastering the Insulin Pump, Howard Wolpert, editor, American Diabetes Association, 2002; Pumping Insulin: Everything You Need For Success With An Insulin Pump, third edition by John Walsh and Ruth Roberts, Torrey Pines Press, San Diego, 2000; Animas IR 1250 User Guide at http://www.animascorp.com/products/pr_insulinpump_IR1250_UserGuide.shtml; Animas IR 1200 Insulin on Board (IOB), Clinical Tips PN 420-151-00 Rev. A; Minimed Paradigm 522 and 722 Insulin Pumps User Guide at http://www.minimed.com/pdf/x22_user_guide.pdf; Deltec Cosmo Insulin Pump User Manual at http://www.cozmore.com/fileUpload/manual—5291-51A.pdf. These references and other references cited within this application are hereby incorporated herein by reference.
In order to adequately describe the present invention, indicate how it differs from the art, and explain its advantages over the art, it is helpful to discuss insulin pharmacodynamics and IOB in greater detail. Unfortunately, IOB has been described inconsistently and misleadingly. IOB has been variously described as the amount of insulin remaining in the body from previous boluses, the amount of insulin still active in the body from previous boluses, and the amount of insulin that has already been delivered to the body, but which has not yet been used. These descriptions differ from one another, and none of them provides a rigorous definition. The way IOB is understood by a skilled insulin pump user is as an insulin credit for the subsequent effect of bolus insulin infused recently enough to have not yet exerted its full effect. Note that its effect is the key to defining and quantifying IOB insulin. Likewise, the present invention focuses on insulin from the standpoint of its effect.
Researchers have developed a gold standard method to measure the effect of insulin—the euglycemic glucose clamp method (L. Heinemann, et al., Diabetes Technology & Therapeutics 2004, 6, 698-718; M. K. Frohnauer, et al., Diabetes Technology & Therapeutics 2001, 3, 419-429; A. D. Frick, et al., Diabetes, 2003, 52, suppl. 1, 511-P; L. Nosek, et al., Diabetes, 2003, 52, suppl. 1, 551-P; T. Heise, et al., Diabetes, 2005, 54, suppl. 1, 588-P; R. H. A. Becker, et al., Diabetes, 2005, 54, suppl. 1, 1367-P; R. N. Bergman, et al., Am. J. Physiol. 1979, 236, E667-E677; K. L. Swan, et al., Diabetes, 2007, 56, suppl. 1, 293-OR; 0. Osterberg, et al., J. Pharmacokinetics and Pharmacodynamics, 2003, 30, 221-235; C. Homko, at al., Diabetes Care, 2003, 26, 2027-2031). There have been several publications of euglycemic glucose clamp studies that measure the effects of subcutaneously bolused rapid-acting types of insulin in Type I diabetes patients. These experiments are typically carried out in the absence of food and unusual physical activity influences. Prior to the experimental insulin bolus, a continuous infusion of basal insulin is adjusted to establish a constant, normal BGC. The experimental insulin bolus is then given, and BGC is maintained in the normal range by intravenous infusion of glucose to compensate for net glucose uptake from the blood in response to the insulin bolus. The glucose infusion rate (GIR) required to do so is recorded. Graphs of the GIR as a function of time define the pharmacodynamic effect (a.k.a. time-action) profiles of the various types of insulin, including the rapid-acting insulin analogs and formulations. As discussed below, such graphs can provide a basis for the way art insulin pumps calculate IOB, as well as provide a basis for calculations under the present invention.
It is widely appreciated that in a euglycemic glucose clamp study, GIR depends not only on the type of insulin administered, the route of administration, and the length of time after insulin administration at which GIR is measured, but also minimally on the amount of insulin administered and the patient's insulin sensitivity. Insulin sensitivity has been defined in several different ways. One way, as a rate of net glucose uptake at a given blood concentration of insulin per kilogram of body mass, illustrates that the patient's body mass and factors that affect the patient's blood concentration of insulin, such as clearance rate, also play a role in determining GIR. To avoid confusion and for the sake of simplicity, the term “insulin responsiveness” (RI) is employed in this specification. As employed here, “insulin responsiveness” captures all of the factors that would affect GIR for a specific patient taking a specific type of insulin by a specific route of administration, except for the amount of insulin administered and the length of time after insulin administration. “Insulin responsiveness” reflects the patient's body mass, the patient's insulin sensitivity (according to the definition above), and all other patient-specific and insulin-specific factors that affect GIR, including the type of insulin, its route of administration (generally subcutaneous for typical insulin pump users), and the rate at which it is cleared from the patient's body.
By the nature of the euglycemic glucose clamp experiment, GIR equals the rate of net glucose uptake (grams per minute). The area under the GIR versus time curve, or put another way, the integral of GIR over time (t, in minutes), from the time of insulin infusion until such time as the pharmacodynamic effect of that insulin is exhausted, equals the total amount of net glucose uptake (grams) in response to the insulin bolus. As an approximation, it is often assumed that total net glucose uptake is proportional to the insulin bolus amount. This assumption of approximate proportionality is consistent with both the insulin-to-carbohydrate ratio concept and also the high blood glucose correction bolus concept, in which the absolute decrease in BGC is proportional to the amount of correction bolus insulin, independent of the initial BGC. These two concepts form the backbone of insulin therapy in Type I diabetes. It is noteworthy that the insulin-to-carbohydrate ratio concept, while imperfect, works best when only carbohydrate is consumed; in a euglycemic glucose clamp study nothing is eaten, and only glucose is infused. Therefore, the approximation that total net glucose uptake is proportional to the insulin bolus amount is reasonable in this context. If RI is constant throughout the duration of insulin action, as it typically is in a euglycemic glucose clamp study, then the integral of GIR over time (total glucose infused=total net glucose uptake, in grams) from the time of insulin infusion (t0) until such time as the pharmacodynamic effect of that insulin is exhausted (too), equals RI (insulin responsiveness, in grams of net glucose uptake per unit of insulin bolused) multiplied by Ii (amount of insulin bolused, in units):
            ∫              t        ⁢                                  ⁢        0                    t        ⁢                                  ⁢        ∞              ⁢                  [                  G          ⁢                                          ⁢          I          ⁢                                          ⁢          R                ]            ⁢              ⅆ        t              =            R      I        ·                  I        i            .      Thus, RI can be thought of as analogous to an insulin-to-carbohydrate ratio, or more accurately, a carbohydrate-to-insulin ratio.
The preceding discussion considers the entire bolus of insulin and its entire effect. However, a formal definition of IOB and a description of the present invention within the euglycemic glucose clamp framework, require a more general treatment of the relationship between GIR, Ii, RI, and time to make it possible to analyze situations in which only part of the pharmacodynamic effect of a dose of insulin has been realized. Toward that end, it is helpful to introduce a new term, “pharmacodynamic insulin unit equivalents”, abbreviated PDIUE, which is defined below. It should be appreciated that although it is convenient to formally define IOB and PDIUE within the euglycemic glucose clamp framework, both IOB and PDIUE, and the concepts they represent, have wide applicability, as exemplified in this specification.
One way to think of PDIUE is as an accounting of insulin amounts allocated to intervals of time according to the pharmacodynamic effect of the insulin over those time intervals. Therefore, the quantity PDIUE is expressed in units, and over the full action time of a bolus of insulin, the total amount of PDIUE must equal the amount of the insulin bolus:
            ∫              t        ⁢                                  ⁢        0                    t        ⁢                                  ⁢        ∞              ⁢                  [                              ⅆ                          (              PDIUE              )                                /                      ⅆ            t                          ]            ⁢              ⅆ        t              =            I      i        .  Thus,
      ∫          t      ⁢                          ⁢      0              t      ⁢                          ⁢      ∞        ⁢            [                        ⅆ                      (            PDIUE            )                          /                  ⅆ          t                    ]        ⁢          ⅆ      t      represents the full insulin bolus from a pharmacodynamic, rather than dosing, perspective. Like PDIUE itself, the quantity ∫[d(PDIUE)/dt] dt is expressed in units.
The way in which PDIUE from an insulin bolus is allocated to time intervals can be determined in a euglycemic glucose clamp study, and the euglycemic glucose clamp framework is ideal for defining PDIUE in a rigorous and quantitative manner. PDIUE may be defined within the euglycemic glucose clamp framework by its relationship to Ii, GIR, RI, and time in a general treatment in which the time intervals considered need not begin with the time of the insulin bolus nor end with a time at which the pharmacodynamic effect of the insulin bolus is exhausted, and in which GIR, RI, and PDIUE all may vary with time, although RI, because of the nature of a euglycemic glucose clamp experiment, generally will not vary. Specifically, PDIUE is defined within the euglycemic glucose clamp framework by two simultaneous equations:
                                                        ∫                              t                ⁢                                                                  ⁢                0                                            t                ⁢                                                                  ⁢                ∞                                      ⁢                                          [                                                      ⅆ                                          (                      PDIUE                      )                                                        /                                      ⅆ                    t                                                  ]                            ⁢                              ⅆ                t                                              =                      I            i                          ,                            equation        ⁢                                  ⁢        1            which is discussed above, and
                                                        ∫                              t                ⁢                                                                  ⁢                1                                            t                ⁢                                                                  ⁢                2                                      ⁢                                          [                                  G                  ⁢                                                                          ⁢                  I                  ⁢                                                                          ⁢                  R                                ]                            ⁢                              ⅆ                t                                              =                                    ∫                              t                ⁢                                                                  ⁢                1                                            t                ⁢                                                                  ⁢                2                                      ⁢                                          [                                                      R                    I                                    ·                                                            ⅆ                                              (                        PDIUE                        )                                                              /                                          ⅆ                      t                                                                      ]                            ⁢                              ⅆ                t                                                    ,                            equation        ⁢                                  ⁢        2            wherein t1 and t2 are the bounds of a time interval. Equation 2 derives from the fact that in a euglycemic glucose clamp experiment, over any time interval, the amount of glucose infused,
            ∫              t        ⁢                                  ⁢        1                    t        ⁢                                  ⁢        2              ⁢                  [                  G          ⁢                                          ⁢          I          ⁢                                          ⁢          R                ]            ⁢              ⅆ        t              ,must equal the amount of net glucose uptake, which is
      ∫          t      ⁢                          ⁢      1              t      ⁢                          ⁢      2        ⁢            [                        R          1                ·                              ⅆ                          (              PDIUE              )                                /                      ⅆ            t                              ]        ⁢                  ⅆ        t            .      The amount of net glucose uptake,
            ∫              t        ⁢                                  ⁢        1                    t        ⁢                                  ⁢        2              ⁢                  [                              R            I                    ·                                    ⅆ                              (                PDIUE                )                                      /                          ⅆ              t                                      ]            ⁢              ⅆ        t              ,is by definition the integral of the rate of insulin action; that rate is expressed here as RI·d(PDIUE)/dt. In turn, the rate of insulin action is the product of insulin responsiveness, RI, and a “rate of insulin usage” in the pharmacodynamic sense, expressed as d(PDIUE)/dt. Thus, d(PDIUE)/dt represents the “rate of insulin usage” in the pharmacodynamic sense, and accordingly, the quantity d(PDIUE)/dt is expressed in units per minute or per hour. (“Rate of PDIUE expenditure” is used herein synonymously with d(PDIUE)/dt.) This pharmacodynamic notion of “insulin usage” connects the definition of PDIUE with one of the ways in which IOB has been described, “the amount of insulin that has already been delivered to the body, but which has not yet been used” (see above). The concept of PDIUE may also be grasped by thinking of
      ∫          t      ⁢                          ⁢      1              t      ⁢                          ⁢      2        ⁢            [                        ⅆ                      (            PDIUE            )                          /                  ⅆ          t                    ]        ⁢          ⅆ      t      as “an amount of insulin usage” in the pharmacodynamic sense over the time interval from t1 to t2, hence the term, “pharmacodynamic insulin unit equivalents”. (“Amount of PDIUE expenditure” is used herein synonymously with
            ∫              t        ⁢                                  ⁢        1                    t        ⁢                                  ⁢        2              ⁢                  [                              ⅆ                          (                              P                ⁢                                                                  ⁢                D                ⁢                                                                  ⁢                I                ⁢                                                                  ⁢                U                ⁢                                                                  ⁢                E                            )                                /                      ⅆ            t                          ]            ⁢                          ⁢                        ⅆ          t                .              )Importantly, in the context of PDIUE discussion, the phrases “amount of insulin usage”, “rate of insulin usage”, “insulin used”, and the like, are meant to describe amounts of insulin as allocated to time intervals according to pharmacodynamic effect, such as can be measured in a euglycemic glucose clamp study. These phrases are not meant to describe amounts of insulin infused during particular time intervals or amounts of insulin allocated to time intervals based on pharmacokinetic disposition, such as an amount of insulin cleared during a particular time interval.
For example, if a 10.0 unit bolus of insulin is given at noon, and GIR rises from and falls back to zero by 4 PM, and between noon and 4 PM total net glucose uptake is 100 grams with 35 of those 100 grams being taken up between 1 PM and 2 PM, then assuming RI to be constant, 35% or 3.5 units of PDIUE from the 10.0 unit bolus is allocated to the time interval from 1 PM to 2 PM. That is,
            ∫              t        ⁢                                  ⁢        1                    t        ⁢                                  ⁢        2              ⁢                  [                              ⅆ                          (                              P                ⁢                                                                  ⁢                D                ⁢                                                                  ⁢                I                ⁢                                                                  ⁢                U                ⁢                                                                  ⁢                E                            )                                /                      ⅆ            t                          ]            ⁢                          ⁢              ⅆ        t              =      3.5    ⁢                  ⁢    units  when t1 is 1 PM and t2 is 2 PM. Also, on average, d(PDIUE)/dt over this time interval is 3.5 units per hour. Note that PDIUE amounts reflect directly the effect of insulin during the time interval and do not reflect directly either the amount of insulin infused during the time interval (none between 1 PM and 2 PM in this example) or the amount of insulin present in or cleared from the body during the time interval (unknown).
The concept of PDIUE is a valuable one for defining IOB within the euglycemic glucose clamp framework. If IOB is understood as an insulin credit for the subsequent effect of bolus insulin infused recently enough to have not yet exerted its full effect, then IOB may be defined as a special case of
      ∫          t      ⁢                          ⁢      1              t      ⁢                          ⁢      2        ⁢            [                        ⅆ                      (                          P              ⁢                                                          ⁢              D              ⁢                                                          ⁢              I              ⁢                                                          ⁢              U              ⁢                                                          ⁢              E                        )                          /                  ⅆ          t                    ]        ⁢                  ⁢          ⅆ      t      in which t1 is the then present time of calculation, tc, and t2 is t∞, a subsequent time when the effect of the bolused insulin is exhausted:
            ∫      tc              t        ⁢                                  ⁢        ∞              ⁢                  [                              ⅆ                          (                              P                ⁢                                                                  ⁢                D                ⁢                                                                  ⁢                I                ⁢                                                                  ⁢                U                ⁢                                                                  ⁢                E                            )                                /                      ⅆ            t                          ]            ⁢                          ⁢              ⅆ        t              =      I    ⁢                  ⁢    O    ⁢                  ⁢          B      .      In other words, the number of units of IOB insulin is the number of units of PDIUE from the then present time of calculation until such time as the effect of bolus insulin is exhausted.
Although the euglycemic glucose clamp framework provides a convenient context within which define both PDIUE and IOB, both terms have wide applicability, and the effect of both PDIUE and IOB insulin may vary with circumstance. Either one may decrease BGC, dispose of glucose from food already eaten, dispose of glucose from food to be eaten, compensate for diminished insulin responsiveness, etc., or perform two or more of these functions simultaneously. PDIUE and IOB insulin quantities do not depend on the BGC, food eaten, or insulin responsiveness, but rather on amounts of insulin bolused, time elapsed since bolusing, and the pharmacodynamic time-action profile of the specific type of insulin infused in the specific patient by their specific route of administration, as could be measured in a euglycemic glucose clamp study if one were performed. Whether or not a euglycemic glucose clamp study actually is performed does not affect PDIUE and IOB insulin quantities. Furthermore, many of the concepts and relationships regarding PDIUE discussed above in the context of a euglycemic glucose clamp experiment hold true generally. For instance, regardless of the circumstances, d(PDIUE)/dt can be considered to represent “a rate of insulin usage” in the pharmacodynamic sense;
      ∫          t      ⁢                          ⁢      1              t      ⁢                          ⁢      2        ⁢            [                        ⅆ                      (                          P              ⁢                                                          ⁢              D              ⁢                                                          ⁢              I              ⁢                                                          ⁢              U              ⁢                                                          ⁢              E                        )                          /                  ⅆ          t                    ]        ⁢                  ⁢          ⅆ      t      can be understood as “an amount of insulin usage” in the pharmacodynamic sense from t1 to t2; the total number of units of PDIUE from an insulin bolus equals the number of units of insulin bolused, that is,
                    ∫                  t          ⁢                                          ⁢          0                          t          ⁢                                          ⁢          ∞                    ⁢                        [                                    ⅆ                              (                                  P                  ⁢                                                                          ⁢                  D                  ⁢                                                                          ⁢                  I                  ⁢                                                                          ⁢                  U                  ⁢                                                                          ⁢                  E                                )                                      /                          ⅆ              t                                ]                ⁢                                  ⁢                  ⅆ          t                      =          I      i        ;and the number of units of IOB is the number of units of PDIUE, or the “amount of insulin usage” in the pharmacodynamic sense, from the then present time of calculation until a subsequent time when the effect of bolus insulin is exhausted, that is,
            ∫      tc              t        ⁢                                  ⁢        ∞              ⁢                  [                              ⅆ                          (                              P                ⁢                                                                  ⁢                D                ⁢                                                                  ⁢                I                ⁢                                                                  ⁢                U                ⁢                                                                  ⁢                E                            )                                /                      ⅆ            t                          ]            ⁢                          ⁢              ⅆ        t              =      I    ⁢                  ⁢    O    ⁢                  ⁢          B      .      
It is noteworthy that although the more general concept of
      ∫          t      ⁢                          ⁢      1              t      ⁢                          ⁢      2        ⁢            [                        ⅆ                      (                          P              ⁢                                                          ⁢              D              ⁢                                                          ⁢              I              ⁢                                                          ⁢              U              ⁢                                                          ⁢              E                        )                          /                  ⅆ          t                    ]        ⁢                  ⁢          ⅆ      t      has been disclosed in the context of predicting BGC (see U.S. Pat. No. 6,925,393, U.S. Pat. No. 5,822,715, US 2006/137695), the art does not describe communication of
      ∫          t      ⁢                          ⁢      1              t      ⁢                          ⁢      2        ⁢            [                        ⅆ                      (                          P              ⁢                                                          ⁢              D              ⁢                                                          ⁢              I              ⁢                                                          ⁢              U              ⁢                                                          ⁢              E                        )                          /                  ⅆ          t                    ]        ⁢                  ⁢          ⅆ      t      to a user, except in the special case of IOB.
Now consider further the scope and limitations of the IOB feature of art insulin pumps with respect to information provided, user options, and recommended application. Art insulin pumps inform a user about current IOB and the amount of time until current IOB declines to zero. The display of past and future IOB values has not been described. In other words, art insulin pumps do not display what IOB was or will be at any time other than the current clock time of the insulin pump.
Art insulin pumps provide the option for a user to set the maximum duration of IOB, that is, the amount of time after an insulin bolus until the effect of that bolus is considered to be exhausted. In other words, art insulin pumps allow a user to shorten or lengthen an internal reference insulin time-action profile that is used to calculate IOB. This adjustment is to be made based on personal experience and/or the advice of a healthcare professional.
According to the art, the principal application for the IOB feature is avoidance of hypoglycemia. An insulin pump user is advised to consider IOB as an insulin credit which, when included in an analysis of carbohydrate—insulin balance, might alert the user to impending hypoglycemia. Typically, a user is instructed to assume that all of the IOB will function as a correction bolus, lowering BGC by the amount expected under basal conditions, that is, when no meal or unusual physical activity effects are operative. If this assumption suggests that the IOB will overcorrect, causing hypoglycemia, then the user is instructed to take action, such as consumption of carbohydrate. It is, however, frequently the case that BGC is measured and IOB is calculated under non-basal conditions, especially when a recent meal is having an effect. The art sometimes instructs a user to assume that only the IOB from a correction bolus, as opposed to insulin dosed for a meal, will function as a correction bolus at the time of IOB calculation. This assumption rests on the premise that any insulin meant to cover food was well-matched to the meal—that is, the effects on BGC of the meal and the insulin dosed to cover it would continuously offset one another—a sort of pseudobasal condition. However, in reality, it is often the case that insulin dosed for food is not well-matched to the meal and a distinctly non-basal, and non-pseudobasal, condition exists. Moreover, because an IOB calculation informs a user only about his total insulin credit from the then present time of calculation until the effect of bolus insulin is exhausted, IOB calculations provide insufficient information to predict potential shorter term, interim deficiencies or excesses that could result in hyper- or hypoglycemia.
One refinement to the art includes the concept that recommended bolus amounts be calculated considering current IOB and also correcting for the current rate of change of BGC, as determined by a continuous glucose monitor (US 2006/173406). Another provides for the prediction of BGC based on the concept of
            ∫              t        ⁢                                  ⁢        1                    t        ⁢                                  ⁢        2              ⁢                  [                              ⅆ                          (                              P                ⁢                                                                  ⁢                D                ⁢                                                                  ⁢                I                ⁢                                                                  ⁢                U                ⁢                                                                  ⁢                E                            )                                /                      ⅆ            t                          ]            ⁢                          ⁢              ⅆ        t              ,wherein t2 may be other than t∞, thus enabling the prediction of BGC at time points prior to the exhaustion of the effect of bolused insulin (U.S. Pat. No. 6,925,393). In both cases, a basal or pseudobasal condition (as defined above) is assumed, except that in the latter case, the future time dependence of the effect of known amounts of carbohydrate consumed may be figured in, provided that the time course of the introduction of glucose into the blood from the carbohydrate is known. Unfortunately, the management of BGC suffers from several significant problems that are not effectively addressed by the art. The teachings of the art are particularly inadequate when poorly understood or complex meals are consumed. Poorly understood meals, that is, meals having unknown components or unknown component quantities, are inherently difficult to manage BGC after because the art requires an understanding of a meal's composition to determine appropriate insulin dosing. Complex meals, that is, meals having many, diverse components, may be well-understood from the standpoint of composition, but they often include sources of protein and fat. Application of the insulin-to-carbohydrate ratio concept to complex meals frequently fails to maintain BGC within, or even near, the target range, and different complex meals often require different insulin-to-carbohydrate ratios, even when they are consumed at the same time of day without variation in physical activity. Complex meals are troublesome largely because the insulin-to-carbohydrate ratio concept considers only the carbohydrate content of a meal, but the fat and protein content of a meal are also important factors that influence the amount and timing of insulin required. High-fat meals are sometimes best managed by infusing some insulin at mealtime and additional insulin, beyond that calculated with the usual insulin-to-carbohydrate ratio, at later times. Notwithstanding the proposal of calculations (U.S. Pat. No. 6,835,175), the art offers no quantitative rules to guide the dosing of insulin based on consideration of the fat and protein content of meals. Poor understanding of meals and the vagaries of complex meals can lead to severe hyper- or hypoglycemia appearing in a fraction of an hour due to imbalances between meal and insulin effects. Furthermore, even when the correct total amount of insulin for a meal is dosed, as judged by target BGC being attained when the meal and insulin effects have been exhausted, in the interim, severe, transient hyper- or hypoglycemia can occur due to imbalances between the meal and insulin effects over short time intervals, for example between 90 and 150 minutes after the start of a meal. Unfortunately, the art does not teach an insulin pump user how to relate insulin pharmacodynamic information to BGC data in order to evaluate in quantitative terms the opposing influences of food and insulin over short time intervals.
Independently of meal effects, the management of BGC under conditions of physical activity variation and other circumstances, such as hormonal fluctuation and extreme emotion, is complicated in ways that are also not reliably addressed in a quantitative manner by the teachings of the art. As a result, when these factors are at play, severe hyper- or hypoglycemia can crop up in a fraction of an hour. The art does not teach an insulin pump user how to relate insulin pharmacodynamic information to BGC data in order to quantitatively evaluate the interplay of insulin effects, physical activity, hormonal fluctuation, and extreme emotion effects over short time intervals.
Regarding BGC management both after meals and/or with physical activity variation, according to the art, exact repetition of meals and/or physical activity coupled with learning from trial and error helps to establish standard protocols for insulin dosing that lead to outcomes that are closer to ideal. However, exact repetition is impractical in many situations, and exact repetition inherently limits flexibility. Moreover, each new situation must be worked out by trial and error which, due to the inevitable errors, often results in severe hyper- or hypoglycemia. Consequently, exact repetition coupled with learning from trial and error is a weak, partial solution to the problems of BGC management.
Finally, insulin delivery problems, such as insulin infusion site deterioration, occur occasionally and can be dangerous if not remedied soon enough. Infusion site deterioration leads initially to unexpected hyperglycemia and may lead to subsequent, unexpected hypoglycemia if insulin delivery is slowed, rather than completely blocked. Insulin delivery problems, such as infusion site deterioration, can be corrected once detected, but their detection can be difficult in the context of a flexible lifestyle because BGC is the main indicator of insulin delivery problems, and in the context of a flexible lifestyle, the art does a poor job of teaching how to predict and manage BGC. This makes it difficult for an insulin pump user to determine whether aberrant BGC is due to an insulin delivery problem or due to suboptimal insulin dosing instead. The art does not teach an insulin pump user how to relate insulin pharmacodynamic information from an insulin pump to BGC data and his knowledge of the various factors that affect BGC in order to identify an insulin delivery problem in a timely fashion.
Because the teachings of the art are inadequate to enable even an experienced and skillful insulin pump user to enjoy a flexible lifestyle while consistently and reliably maintaining his BGC within or near the target range, new tools are needed. Toward this end, the present invention is disclosed.